CYCLOSPORIN A, A POWERFUL IMMUNOSUPPRESSANT IN VTVO AND IN VITRO IN THE DOG, FAILS TO INDUCE TOLERANCE

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Abstract
Cyclosporin A (Cy A) was evaluated in dogs for its effectiveness in prolonging skin graft survival from DLA-nonidentical, unrelated donors and in reversing “rejection crises.” Cy A was given in courses of 21 days. Dogs were monitored in vitro with mixed leukocyte cultures (MLCs), and indirect cell-mediated lympholysis (CML). Grafts remained viable throughout the first Cy A course. Signs of rejection developed on days 27 to 33. These were reversed in three of four dogs by a second course of Cy A. Second and third rejection crises following subsequent courses of Cy A were also reversed. After stopping Cy A first-set grafts were ultimately rejected, by days 83 to 114. Second-set graft survival was also prolonged by Cy A and rejection crises were reversed by additional Cy A courses. After stopping Cy A second-set grafts were rejected. Median graft survival in 35 untreated dogs was 12 days for the first and 8 days for the second set (24 dogs). Lymphocytes from all Cy A-treated dogs showed normal reactivity in MLCs and CML against lymphocytes from skin graft donors and unrelated dogs when set up in normal serum. In serum from Cy A-treated dogs, MLC and CML reactivities were abrogated. Similar suppression was seen with Cy A added in vitro. Mitogen-induced blastogenesis was only mildly suppressed by serum from Cy A-treated dogs. We conclude that Cy A is a powerful immunosuppressant in the dog in vivo and in vitro but that it fails to induce persistent immunological unresponsiveness. Rather, immunosuppression appears to depend upon the continued presence of the drug.